Dysfunction of the brain ascending dopaminergic system is responsible for a wide array of severe neuropsychiatric conditions, affecting millions of people in North America and Europe. Schizophrenia, for example, is a chronic and debilitating neurological disorder that is characterized by the presentation of positive symptoms, negative symptoms and cognitive impairments. It is believed that an imbalance in the dopaminergic system (subcortical excess and cortical deficiency) is involved in the pathophysiological processes of schizophrenia (see, for example, Abi-Dargham, A., 2004, Int. J. Neuropsychopharmacol., 7 Suppl. 1:S1-S5). It is believed that decreased activity of the D1 receptors in the PFC may play a significant role in the expression of negative symptoms and cognitive deficits in schizophrenic patients. However, almost all currently available antipsychotic drugs are D2 dopamine receptor antagonist with some extent of serotonergic activities. As such, these antipsychotic drugs are only moderately effective in treating the positive symptoms of schizophrenia and are not effective in treating the negative symptoms and cognitive deficits in these patients.
Cognitive impairment mediated by hypoactivity in the prefronal cortex (PFC) is commonly observed in schizophrenic individuals (Goldman-Rakic, 1999, Biol Psych 46(5):650-661; Weinberger et al., 2001, Biol Psych 50(11):825-844; Seamans and Yang, 2004, Prog in Neurobiol 74(1):1-58). Clinical data suggest a beneficial relationship between improved cognition and positive social and clinical outcomes (Andreasen, 2000, Brain Res Brain Res Rev 31(2-3):106-112), but development of effective treatments to address cognitive deficits seen in psychotic patients has been challenging. Preclinical studies provide strong support for the hypothesis that optimal dopamine concentrations in the frontal lobes facilitate cognitive function (Goldman-Rakic, 1995, Neuron 14(3):477-485; Phillips et al., 2004, J Neurosci, 24(2):547-553). Increasing the bioavailability of dopamine or local stimulation of dopamine receptors in the frontal cortex is effective in animals to improve cognitive function in circumstances where cognitive performance is suboptimal (Fletcher et al., 1996, J Neurosci 16(21):7055-7062; Hotte et al., 2005, Neurobiol Learn Mem 84(2):85-92; Floresco & Phillips, 2001, Behav Neurosci 204(2):396-409; Tunbridge et al., 2004, J Neurosci 24(23):5331-5335; Lapish et al., 2009, Psychopharm 202(1-3):521-530). Accordingly, pharmacotherapies that restore optimal PFC dopamine levels or activity at PFC dopamine receptors, may yield an effective pro-cognitive treatment strategy.
Tetrahydroprotoberberines (THPBs) are a series of alkaloids isolated from plants. Chemically, the compound l-stepholidine (also known as (−)-stepholidine or (S)-stepholidine), which is isolated from roots of the Chinese herb Stephania intermedica lo, is a prototypical member of the THPBs characterized by a tetracyclic ring skeleton, an isoquinoline core, and a chiral carbon at C(14) (see FIG. 1). l-stepholidine (l-SPD) appears to exhibit unique pharmacological activities in its ability to elicit activities in both the D1 and D2 receptors in vitro and in vivo (Gao et al., 2007, Acta Pharmacol Sin., 28(5):627-33; Jin et al., 2002, Trends Pharmacol Sci., 23(1):4-7; Mo et al., 2007, Curr Med Chem., 14(28):2996-3002; Mo et al., 2008, Neurobiol Aging, August 14, [Epub ahead of print]). Synthesis of racemic dl-SPD and enantioselective synthesis of l-SPD have been reported (Chiang & Brochmann-Hanssen, 1977, J Org Chem., 42:3190-3194; Cheng et al., 2009, J Org Chem., 74(23):9225-8).
l-govadine is another example of a THPB that has been isolated from natural sources (Hu et al., 1998, Zhongguo Yaowu Huaxue Zazhi, 8:190-195). The synthesis of racemic govadine has been reported (Hu et al., 1998, ibid, Kametani & Satoh, 1967, J. Pharm. Soc. Jpn, 179; Chiang & Brochmann-Hanssen, 1977, ibid.; Chiang, et al., 1978, Taiwan Yaoxue Zazhi, 54:30; Kametani & Ihara, 1980, J. Chem. Soc., Perkin Trans. 1, 629; Yongzhou, 1998, Chinese J. Med. Chem., 8:190; Mehra, et al., 1976, Indian J. Chem., Sect B, 14B:216). These routes access the desired tetrahydroisoquinoline core utilizing racemic reductions of the corresponding dihydroisoquinoline.
Investigations into the activity of certain THPBs has suggested that the l- and d-enantiomers of the compounds may possess different activities. Clement-Cormier et al. (1979, Biochemical Pharmacology, 28:3123-3129) reported that optical isomers of 2,3,10,11-THPB showed different activities in the antagonism of the dopamine-sensitive adenylate cyclase, as did positional isomers and methylated derivatives.
Jin et al. (1984, Scientia Sinica, 29:1054-1064) investigated the activities of l- and d-tetrahydropalmitine (THP) on the dopaminergic system. The results obtained in this study indicated that d-THP had no affinity for the dopamine receptors and demonstrated different effects on DOPA accumulation and dopamine levels than the l-isomer, leading the authors to conclude that l-THP is a dopamine receptor antagonist, whereas d-THP is a dopamine depletor. Similarly, Shou-Xi et al. (1989, Acta Pharmalogica Sinica, 10:104-110) compared the affinity of l- and d-THP for the dopamine D1 and D2 receptors and concluded that d-THP has no affinity for the D2 receptor. Later functional studies on l- and d-THP led to the same conclusion (Sun et al., 1992, Acta Pharmalogica Sinica, 13:292-297; Cao et al., 1993, Asia Pacific J Pharmacology, 8:61-65).
Zhang and Jin (1996, Acta Pharmalogica Sinica, 17:18-22) compared the effects of (−)-SPD (l-SPD) with chloroscoulerine (CSL) enantiomers on the dopamine D1 and D2 receptors and concluded that CSL enantiomers, like l-SPD, are D1/D2 mixed antagonists, and that while all the compounds tested were D2 antagonists, (+)-CSL was a very weak one. Chen et al. (1999, Acta Pharmalogica Sinica, 20:884-888) investigated the pharmacological behaviour of CSL enantiomers on dopamine receptors, in particular the activity of CSL enantiomers in behavioural tests in mice and rats. The study determined that d-CSL had a weaker affinity for the D1 receptor and a much weaker affinity for the D2 receptor than l-CSL, and that while both enantiomers inhibited apomorphine-induced stereotypy, catalepsy and amphetamine-induced jumping in test animals, d-CSL showed a weaker effect in all tests.
l-SPD has been the subject of extensive preclinical research primarily motivated by its ability to dynamically target dopamine D1 and D2 receptors (Mo et al., 2007, Current Medicinal Chemistry, 14:2996-3002; Natesan et al., 2008, Psychopharmacology, 199:275-289). Preclinical measures of antipsychotic efficacy such as attenuated psychostimulant induced locomotion, disrupted CAR, and the induction of catalepsy, provide evidence of l-SPD's dopamine D2 antagonism (Natesan et al. 2008, ibid.).
dl-Govadine, which has a core structure similar to that of l-SPD, has been characterized as a noradrenaline α1 antagonist in peripheral cardiovascular tissue (Guh et al., 1999, European J. Pharmacology, 374:503-510. Ko et al., 1996, J. Pharmacy and Pharmacology, 48:629-634). Receptor binding assays showed dl-govadine to have a higher affinity than l-SPD for the dopamine D1 receptor, but a lower affinity for the D2 receptor (Hu et al., 1998, ibid).
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.